Endocrine Disruption

Actions : Docking :: Receptor Binding
  1. G Proteins
  2. G Protein-Coupled Receptors
  3. References

Steroid Receptors On the Cell Surface

Surface receptors are embedded in a cell's outer membrane. Hormones binding to receptors nestled in the membrane can initiate gene expression or spark molecular signal cascades - lightening fast chain reactions of chemical communication inside the cell that immediately change cell functions. Cells respond to genetic expression in hours to days whereas the response to the membrane-bound steroid receptor’s nongenomic signals occurs very rapidly, usually in just seconds to minutes.

The complex, cascading signal begins when hormones, or other signaling messengers, outside the cell bind with and activate certain cell surface receptors. The receptors, in turn, interact with special signaling molecules inside the cell called intracellular second messengers, including guanylyl nucleotide regulatory proteins (G proteins), inositol triphosphate, and cyclic adenosine monophosphate (cAMP). The second messengers then switch on the kinase enzymes. These specialized proteins phosphorylate - add phosphorus to - other enzymes. Adding phosphorous turns on many different kinds of cell enzymes that regulate a variety of responses including cell growth, electrolyte movement across the cell membrane, and hormone secretion.

G Proteins

G proteinsG proteins are regulatory proteins found in the inside surface of the plasma membrane. They are directly associated with many types of plasma membrane receptors including those that interact with steroid hormones such as G protein coupled receptors (GPCRs). The specialized G proteins direct activities of other proteins through on/off signals evoked by the transfer of guanosine diphosphate (GDP) to guanosine triphosphate (GTP).

CAPTION: G proteins, found on the inside surface of the cell membrane, turn other proteins off and on. CREDIT: Tulane/Xavier Center for Bioenvironmental Research.

G proteins have three subunits: alpha (α), beta (β), and gamma (γ). In the absence of hormone binding to the G protein coupled receptor, the G protein is inactive: its alpha subunit is bound to GDP and the three subunits are tightly associated. Hormone docking to the receptor activates the G protein allowing the alpha subunit to exchange GDP for GTP. At this point, the alpha subunit disconnects from the beta-gamma subunits, which remain in the cell membrane. The alpha subunit can then activate or inhibit enzymes in the cell cytoplasm, starting or stopping specific signaling pathways.

G Protein-Coupled Receptors

Three kinds of receptors with different molecular structures interact with steroid hormones at the cell surface. Two of the receptors, the G protein-coupled receptors (GPRs) and the G protein-coupled receptor-like receptors, are only found in the cell’s plasma membrane. The third is simply a nuclear steroid receptor tightly lodged in the cell membrane (Cato et al. 2002; Hammes 2003; Toran-Allerand 2004; Zhu et al. 2003a, 2003b). The receptors transverse the membrane and are situated with one end poking to the outside of the cell - where ligand binding occurs - while the other is positioned inside the cell - where the signal is transmitted.

GPRs and their ilk possess the unique property of being able to bind with steroid hormones located outside the cell to initiate and promote fast, nongenetic hormone-like changes inside the cell. Prior to their discovery, how cells without steroid nuclear hormone receptors reacted to hormones perplexed researchers. Prime examples are certain breast cancer cells that lack the nuclear estrogen receptors ERalpha and ERbeta but still grow in response to the estrogen 17-beta estradiol (E2). Why the cells respond to the hormone was a mystery until an estrogen-specific G protein-coupled receptor called GPR30 was identified in the plasma membrane of these cells. When E2 binds to GPR30, a cascade of enzyme activation turns on cell growth (Cato et al. 2002).

Another family of membrane receptors with GPR-like molecular structures binds with and responds to progestin hormones. The progestin membrane receptors (mPRs) trigger internal signaling pathways similar to GPRs rather than invoking gene expression typical of steroid hormone receptors. Like GPRs, these receptors have seven trans-membrane domains. Pertussis toxin, a bacterial poison that prevents certain G proteins from interacting with other second messengers inside the cell, can block their action. However, the receptors are probably an entirely new class of membrane receptor since their amino acid sequence differs from other GPRs.

Researchers first found mPRs in spotted seatrout and deciphered their important role in stimulating fish egg maturation. The complicated series of signals begins when the progestin hormone progesterone binds mPR and activates Gai protein. Gai inhibits activity of the second messenger adenylate cyclase (an enzyme that converts ATP to cAMP and pyrophosphate), decreasing intracellular cAMP levels and reducing protein kinase A (PKA) activity. Lower PKA activity releases phosphatase Cdc25C to dephosphorylate and activate the cell cycle proteins Cdc2 and cyclin B. Active Cdc2 and cyclin B are necessary for germinal vesicle breakdown (dissolution of the nucleus) and final oocyte (immature egg) maturation (Zhu et al. 2003a, 2003b).

Fast Signaling Pathway CAPTION: Estrogen activates membrane receptor initiating a protein signaling cascade. (click image for animation) CREDIT: Tulane/Xavier Center for Bioenvironmental Research.

GPR-like mPRs have been discovered in a variety of backboned animals, including several kinds of fish, in frogs and mammals (pigs, mice), and in human tissues in the reproductive tract, kidneys, intestine, and brain. One type of mPR rouses both human and fish sperm, making the sperm competent to fertilize eggs (Zhu et al. 2003a). The mPR in fish sperm, though, can be blocked by foreign chemicals, particularly the organochlorine insecticide kepone and o,p’-DDD, a metabolite of the insecticide o,p’-DDT (Das and Thomas 1999).

  • Cato A, Nestl A, and Mink S. 2002. Rapid actions of steroid receptors in cellular signaling pathways. Science's STKE 2002: re9; doi: 10.1126/stke.2002.138.re9; Available: http://stke.sciencemag.org/cgi/content/full/sigtrans%3b2002/138/re9.
  • Das S and Thomas P. 1999. Pesticides interfere with the nongenomic action of a progestogen on meiotic maturation by binding to its plasma membrane receptor on fish oocytes. Endocrinology 140:1953-1956.
  • Hammes S. 2003. The further redefining of steroid-mediated signaling. Proceedings of the National Academy of Science 100:2168-2170.
  • Toran-Allerand C. 2004. Minireview: A plethora of estrogen receptors in the brain: Where will it end? Endocrinology 145:1069-1074.
  • Zhu Y, Bond J, and Thomas P. 2003a. Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proceedings of the National Academy of Science 100:2237-2242.
  • Zhu Y, Rice C, Pang Y, Pace M, and Thomas P. 2003b. Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes. Proceedings of the National Academy of Science 100:2231-2236.